Rats given an experimental therapy several weeks after their spinal cords were severed showed dramatically greater regrowth of nerve fibers and recovery of function than rats treated immediately after injury, a new study shows. The report suggests that the window of opportunity for treating spinal cord injury may be wider than previously anticipated.

The researchers used a combination therapy of fetal spinal tissue transplants and nerve growth factors, or neurotrophins. Earlier studies in animals have shown that fetal tissue transplants and neurotrophins can improve regrowth of injured neurons in the adult spinal cord, and that some injured neurons can regrow even after long periods of time. However, the new study is the first to show that spinal cord regeneration is actually improved when treatment is postponed until most of the initial injury-related changes in the rat spinal cord and the surrounding environment have stabilized, says Barbara S. Bregman, Ph.D., of Georgetown University Medical Center, who led the study. The work was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the December 1, 2001, issue of The Journal of Neuroscience.*

"This is an exciting finding and gives us hope that similar therapies may ultimately be useful in humans with severe spinal cord trauma," says Audrey S. Penn, M.D., acting director of NINDS. "The surprising and important implication is that therapy may work better if it is delayed."

Dr. Bregman and colleagues studied four groups of adult rats with completely severed spinal cords. One group received no treatment and a second group received immediate treatment with fetal spinal tissue grafts. With the remaining two groups of rats, the wound was cleaned out and scar tissue was removed after intervals of either 2 or 4 weeks. The rats then received fetal spinal cord tissue grafts. All the rats receiving transplants also had infusions of either saline, neurotrophin-3 (NT-3), or brain-derived neurotrophic factor (BDNF) for 2 weeks after the transplants were completed.

Differences in motor function between the groups began to emerge 3 to 4 weeks after the transplants. Animals that received a delayed transplant plus treatment with one of the neurotrophins could partially support their weight on their rear legs and had more coordination between the front and back legs than animals that received immediate treatment. After training, about 20 percent of the animals that received transplants plus neurotrophins after a delay were able to consistently support their weight while walking, and another 30 percent were able to do so some of the time. These animals also were able to support themselves on one limb while stepping on stairs. Animals that received immediate treatment with the combined therapy could sometimes support themselves while walking, but less than rats with the delayed treatment. The rats with immediate combined treatment also were unable to support themselves during stair-climbing. Animals that received transplants without neurotrophins could not support themselves during any steps.

When the rats' spinal cords were examined, most (24 of 27) of the animals that received delayed transplants plus neurotrophins had regenerated nerve fibers, or axons, that reached the spinal cord below the transplant. Compared with animals that received immediate treatment, the average axonal growth in animals with delayed treatment was more than 6 times greater in white matter (so called because it contains nerve fibers coated by a whitish substance called myelin) and 2.6 times greater in gray matter, which does not contain myelin. Surprisingly, the axons below the point of injury regrew into the white matter even though previous work has shown that myelin-associated inhibitory factors can interfere with axon growth. The pattern of axon growth was also better in the rats that received delayed treatment, with more branching and larger, more complex axon clusters. The overall results were not significantly different in the group treated after 4 weeks than in the group treated after 2 weeks.

Although most recovery was seen in animals that regrew fibers across the injury site, there was no obvious correlation between the amount of fiber regrowth in individual animals and the amount of improved function. This suggests that spinal cord circuits can respond to far fewer than the normal number of nerve fibers and that there may be changes, or plasticity, in connections above and below the point of injury that influence the amount of recovery, says Dr. Bregman.

These findings support previous animal studies showing that combination therapy with transplantation and neurotrophins is more effective than either approach by itself. While the findings are promising, much more research will be necessary before this type of therapy could be tested in humans, the researchers say. However, if the results translate to the types of spinal cord injuries experienced in human patients, then the opportunity for improving function after such a devastating injury may be much greater than anyone imagined. Future studies should investigate how regeneration and activity may be combined to improve recovery, says Dr. Bregman.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system. The Institute is celebrating its 50th anniversary this year.